The Experts below are selected from a list of 516 Experts worldwide ranked by ideXlab platform
Michito Hamada - One of the best experts on this subject based on the ideXlab platform.
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Transcription Factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis.
Kidney International, 2020Co-Authors: Toshiaki Usui, Michito Hamada, Naoki Morito, Hossam H. Shawki, Yoshinori Sato, Hiroyasu Tsukaguchi, Hyojung Jeon, Manoj Kumar Yadav, Akihiro Kuno, Yuki TsunakawaAbstract:Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome. Spontaneous remission of FSGS is rare and steroid-resistant FSGS frequently progresses to renal failure. Many inheritable forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. Here, we show that a basic leucine zipper Transcription Factor, MafB, protects against FSGS. MafB expression was found to be decreased in the podocytes of patients with FSGS. Moreover, conditional podocyte-specific MafB-knockout mice developed FSGS with massive proteinuria accompanied by depletion of the slit diaphragm-related proteins (Nphs1 and Magi2), and the podocyte-specific Transcription Factor Tcf21. These findings indicate that MafB plays a crucial role in the pathogenesis of FSGS. Consistent with this, adriamycin-induced FSGS and attendant proteinuria were ameliorated by MafB overexpression in the podocytes of MafB podocyte-specific transgenic mice. Thus, MafB could be a new therapeutic target for FSGS.
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Role of MafB in macrophages.
Experimental Animals, 2020Co-Authors: Michito Hamada, Hyojung Jeon, Manoj Kumar Yadav, Yuki Tsunakawa, Satoru TakahashiAbstract:The Transcription Factor MafB regulates macrophage differentiation. However, studies on the phenotype of MafB-deficient macrophages are still limited. Recently, it was shown that the specific expression of MafB permits macrophages to be distinguished from dendritic cells. In addition, MafB has been reported to be involved in various diseases related to macrophages. Studies using macrophage-specific MafB-deficient mice show that MafB is linked to atherosclerosis, autoimmunity, obesity, and ischemic stroke, all of which exhibit macrophage abnormality. Therefore, MafB is hypothesized to be indispensable for the regulation of macrophages to maintain systemic homeostasis and may serve as an innovative target for treating macrophage-related diseases.
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Transcription Factor MafB may play an important role in secondary hyperparathyroidism
Kidney International, 2018Co-Authors: Naoki Morito, Michito Hamada, Toshiaki Usui, Hossam H. Shawki, Keigyou Yoh, Hisashi Oishi, Masami Ojima, Akiko Fujita, Ryusuke Koshida, Masafumi MurataniAbstract:The Transcription Factor MafB is essential for development of the parathyroid glands, the expression of which persists after morphogenesis and in adult parathyroid glands. However, the function of MafB in adult parathyroid tissue is unclear. To investigate this, we induced chronic kidney disease (CKD) in wild-type and MafB heterozygote ( MafB+/– ) mice by feeding them an adenine-supplemented diet, leading to secondary hyperparathyroidism. The elevated serum creatinine and blood urea nitrogen levels in heterozygous and wild-type mice fed the adenine-supplemented diet were similar. Interestingly, secondary hyperparathyroidism, characterized by serum parathyroid hormone elevation and enlargement of parathyroid glands, was suppressed in MafB+/– mice fed the adenine-supplemented diet compared to similarly fed wild-type littermates. Quantitative RT-PCR and immunohistochemical analyses showed that the increased expression of parathyroid hormone and cyclin D2 in mice with CKD was suppressed in the parathyroid glands of heterozygous CKD mice. A reporter assay indicated that MafB directly regulated parathyroid hormone and cyclin D2 expression. To exclude an effect of a developmental anomaly in MafB+/– mice, we analyzed MafB tamoxifen-induced global knockout mice. Hypocalcemia-stimulated parathyroid hormone secretion was significantly impaired in MafB knockout mice. RNA-sequencing analysis indicated PTH, Gata3 and Gcm2 depletion in the parathyroid glands of MafB knockout mice. Thus, MafB appears to play an important role in secondary hyperparathyroidism by regulation of parathyroid hormone and cyclin D2 expression. Hence, MafB may represent a new therapeutic target in secondary hyperparathyroidism.
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A mutation in Transcription Factor MafB causes Focal Segmental Glomerulosclerosis with Duane Retraction Syndrome.
Kidney International, 2018Co-Authors: Yoshinori Sato, Michito Hamada, Toshiaki Usui, Naoki Morito, Hiroyasu Tsukaguchi, Mai Thi Nhu Tran, Hiroyuki Morita, Koichiro Higasa, Shoichiro Horita, Takao HayashiAbstract:Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease in children and adults. Genetic Factors significantly contribute to early-onset FSGS, but the etiologies of most adult cases remain unknown. Genetic studies of monogenic syndromic FSGS exhibiting extra-renal manifestations have uncovered an unexpected biological role for genes in the development of both podocytes and other cellular lineages. To help define these roles, we studied two unrelated families with FSGS associated with Duane Retraction Syndrome, characterized by impaired horizontal eye movement due to cranial nerve malformation. All four affected individuals developed FSGS and Duane Retraction Syndrome in their first to second decade of life, manifested as restricted abduction together with globe retraction and narrowed palpebral fissure on attempted adduction. Hypoplasia of the abducens nerves and hearing impairment occurred in severely affected individuals. Genetic analyses revealed that affected individuals harbor a rare heterozygous substitution (p.Leu239Pro) in MafB, a leucine zipper Transcription Factor. Luciferase assays with cultured monocytes indicated that the substitution significantly reduced transactivation of the F4/80 promoter, the known MafB recognition element. Additionally, immunohistochemistry indicated reduced MafB expression in the podocytes of patients. Structural modeling suggested that the p.Leu239Pro substitution in the DNA-binding domain possibly interferes with the stability of the adjacent zinc finger. Lastly, podocytes in neonatal mice with p.Leu239Pro displayed impaired differentiation. Thus, MafB mutations impair development and/or maintenance of podocytes, abducens neurons and the inner ear. The interactions between MafB and regulatory elements in these developing organs are likely highly specific based on spatiotemporal requirements.
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MafB is a critical regulator of complement component C1q
Nature Communications, 2017Co-Authors: Mai Thi Nhu Tran, Michito Hamada, Hyojung Jeon, Yuki Tsunakawa, Megumi Nakamura, Risako Shiraishi, Keigo Asano, Motochika Hattori, Yuki Imamura, Risa FujiiAbstract:The Transcription Factor MafB is expressed by monocytes and macrophages. Efferocytosis (apoptotic cell uptake) by macrophages is important for inhibiting the development of autoimmune diseases, and is greatly reduced in MafB-deficient macrophages. Here, we show the expression of the first protein in the classical complement pathway C1q is important for mediating efferocytosis and is reduced in MafB-deficient macrophages. The efferocytosis defect in MafB-deficient macrophages can be rescued by adding serum from wild-type mice, but not by adding serum from C1q-deficient mice. By hemolysis assay we also show that activation of the classical complement pathway is decreased in MafB-deficient mice. In addition, MafB overexpression induces C1q-dependent gene expression and signals that induce C1q genes are less effective in the absence of MafB. We also show that MafB-deficiency can increase glomerular autoimmunity, including anti-nuclear antibody deposition. These results show that MafB is an important regulator of C1q.
Brian Seed - One of the best experts on this subject based on the ideXlab platform.
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the Transcription Factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the Transcription Factor irf3
Nature Immunology, 2010Co-Authors: Brian SeedAbstract:Type I interferons (IFN-α and IFN-β) are key to antiviral immunity. Kim and Seed now demonstrate that the Transcription Factor MafB acts as a metastable switch to control expression of IFN-β. Viral infection induces type I interferons (IFN-α and IFN-β) that recruit unexposed cells in a self-amplifying response. We report that the Transcription Factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of Transcription at the IFNB1 promoter through activity at Transcription Factor AP-1–like sites. Interferon elicitors recruited the Transcription Factor IRF3 to the promoter, whereupon MafB acted as a Transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.
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the Transcription Factor MafB antagonizes antiviral responses by blocking recruitment of coactivators to the Transcription Factor irf3
Nature Immunology, 2010Co-Authors: Hwijin Kim, Brian SeedAbstract:Viral infection induces type I interferons (IFN-alpha and IFN-beta) that recruit unexposed cells in a self-amplifying response. We report that the Transcription Factor MafB thwarts auto-amplification by a metastable switch activity. MafB acted as a weak positive basal regulator of Transcription at the IFNB1 promoter through activity at Transcription Factor AP-1-like sites. Interferon elicitors recruited the Transcription Factor IRF3 to the promoter, whereupon MafB acted as a Transcriptional antagonist, impairing the interaction of coactivators with IRF3. Mathematical modeling supported the view that prepositioning of MafB on the promoter allows the system to respond rapidly to fluctuations in IRF3 activity. Higher expression of MafB in human pancreatic islet beta cells might increase cellular vulnerability to viral infections associated with the etiology of type 1 diabetes.
Sandrine Sarrazin - One of the best experts on this subject based on the ideXlab platform.
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Integration of cell cycle control and cell fate choice in M-CSF-instructed myeloid lineage commitment of hematopoietic stem cells
Experimental Hematology, 2014Co-Authors: Sandrine Sarrazin, Noushine Mossadegh-keller, Prashanth K. Kandalla, Leon Espinosa, Michael SiewekeAbstract:We have shown recently that under hematopoietic stress conditions of infection high systemic levels of M-CSF can directly instruct myeloid gene expression and differentiation preference of HSC by activation of the myeloid master regulator PU.1 (Mossadegh-Keller et al, Nature, 2013), demonstrating that stem cells are direct targets of lineage instruction by cytokines. Moreover, we have shown earlier that HSC deficient for the Transcription Factor MafB are more sensible to M-CSF induced PU.1 activation and myeloid lineage commitment (Sarrazin et al, Cell, 2009). It has also been recently shown that cell cycle length in progenitors can control PU.1 protein accumulation and, as a consequence, myeloid lineage commitment (Kueh et al, Science, 2013). Since MafB is known to control cellular proliferation of mature myeloid cells we investigated whether MafB levels could control cell cycle entry and thus PU.1 accumulation in MCSF instructed-HSC. We monitored cell division and commitment of wt and MafB-/HSC in response to M-CSF by video-microscopy and analyzed mRNA expression of cell cycle regulators by nanofluidic real time PCR of individual HSC. We observed that in absence of MafB, HSC entered the cycle at a higher rate in response to MCSF and showed a gene expression signature typical of cycling cells. In vivo, individual transplantedMafB-/-HSC showedmassively increased and rapid activation of PU.1 in a hematopoieticmicroenvironment of a hostwith high systemic levels ofM-CSF. Furthermore, the commitment of highly purified HSC to PU.1+ cells was dependent onM-CSF signaling in vivo, as demonstrated by use of blocking antibody or chemical inhibitor to specifically block M-CSF receptor signaling in HSC. Taken together our data indicate that MafB affects cytokine instructed cell fate change in HSC by controlling rate of cell cycle entry. These observations reveal novel mechanisms integrating cell cycle control and lineage choice inHSC. Their manipulationmay hold potential for therapeutic modulation ofHSCbehavior under challenge conditions such as transplantation or infection.
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MafB Restricts M-CSF-Dependent Myeloid Commitment Divisions of Hematopoietic Stem Cells
Cell, 2009Co-Authors: Sandrine Sarrazin, Laurent Vanhille, Noushine Mossadegh-keller, Taro Fukao, Athar Aziz, Frédéric Mourcin, Louise K. Modis, Philippe Kastner, Susan Chan, Estelle DuprezAbstract:While hematopoietic stem cell (HSC) self-renewal is well studied, it remains unknown whether distinct control mechanisms enable HSC divisions that generate progeny cells with specific lineage bias. Here, we report that the monocytic Transcription Factor MafB specifically restricts the ability of M-CSF to instruct myeloid commitment divisions in HSCs. MafB deficiency specifically enhanced sensitivity to M-CSF and caused activation of the myeloid master-regulator PU.1 in HSCs in vivo. Single-cell analysis revealed that reduced MafB levels enabled M-CSF to instruct divisions producing asymmetric daughter pairs with one PU.1(+) cell. As a consequence, MafB(-/-) HSCs showed a PU.1 and M-CSF receptor-dependent competitive repopulation advantage specifically in the myelomonocytic, but not T lymphoid or erythroid, compartment. Lineage-biased repopulation advantage was progressive, maintained long term, and serially transplantable. Together, this indicates that an integrated Transcription Factor/cytokine circuit can control the rate of specific HSC commitment divisions without compromising other lineages or self-renewal.
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SUMO modification regulates MafB-driven macrophage differentiation by enabling Myb-dependent Transcriptional repression.
Molecular and Cellular Biology, 2007Co-Authors: Silke Tillmanns, Sandrine Sarrazin, Laurent Vanhille, Claas Otto, Youssef Bakri, Ellis Jaffray, Camille Du Roure, Ronald T. Hay, Michael H. SiewekeAbstract:During the execution of differentiation programs, lineage-specific Transcription Factors are in competition with antagonistic Factors that drive progenitor proliferation. Thus, the myeloid Transcription Factor MafB promotes macrophage differentiation of myeloid progenitors, but a constitutively active Myb Transcription Factor (v-Myb) can maintain proliferation and block differentiation. Little is known, however, about the regulatory mechanisms that control such competing activities. Here we report that the small ubiquitin-like protein SUMO-1 can modify MafB in vitro and in vivo on lysines 32 and 297. The absence of MafB SUMO modification increased MafB-driven transactivation and macrophage differentiation potential but inhibited cell cycle progression and myeloid progenitor growth. Furthermore, we observed that direct repression of MafB transactivation by v-Myb was strictly dependent on MafB SUMO modification. Consequently, a SUMOylation-deficient MafB K32R K297R (K32,297R) mutant could specify macrophage fate even after activation of inducible Myb alleles and resist their differentiation-inhibiting activity. Our findings suggest that SUMO modification of MafB affects the balance between myeloid progenitor expansion and terminal macrophage differentiation by controlling MafB transactivation capacity and susceptibility to Myb repression. SUMO modification of lineage-specific Transcription Factors may thus modulate Transcription Factor antagonism to control tissue homeostasis in the hematopoietic system.
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Development of macrophages with altered actin organization in the absence of MafB.
Molecular and Cellular Biology, 2006Co-Authors: Athar Aziz, Louise M Kelly, Sandrine Sarrazin, Laurent Vanhille, Peer Mohideen, Claas Otto, Youssef Bakri, Noushine Mossadegh, Michael H. SiewekeAbstract:In the hematopoietic system the bZip Transcription Factor MafB is selectively expressed at high levels in monocytes and macrophages and promotes macrophage differentiation in myeloid progenitors, whereas a dominant-negative allele can inhibit this process. To analyze the requirement of MafB for macrophage development, we generated MafB-deficient mice and, due to their neonatal lethal phenotype, analyzed macrophage differentiation in vitro, in the embryo, and in reconstituted mice. Surprisingly we observed in vitro differentiation of macrophages from E14.5 fetal liver (FL) cells and E18.5 splenocytes. Furthermore we found normal numbers of F4/80(+)/Mac-1(+) macrophages and monocytes in fetal liver, spleen, and blood as well as in bone marrow, spleen, and peritoneum of adult MafB(-/-) FL reconstituted mice. MafB(-/-) macrophages showed intact basic macrophage functions such as phagocytosis of latex beads or Listeria monocytogenes and nitric oxide production in response to lipopolysaccharide. By contrast, MafB(-/-) macrophages expressed increased levels of multiple genes involved in actin organization. Consistent with this, phalloidin staining revealed an altered morphology involving increased numbers of branched protrusions of MafB(-/-) macrophages in response to macrophage colony-stimulating Factor. Together these data point to an unexpected redundancy of MafB function in macrophage differentiation and a previously unknown role in actin-dependent macrophage morphology.
Megumi Nakamura - One of the best experts on this subject based on the ideXlab platform.
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Transcription Factor MafB is a marker of tumor-associated macrophages in both mouse and humans.
Biochemical and Biophysical Research Communications, 2020Co-Authors: Manoj Kumar Yadav, Hyojung Jeon, Yuki Tsunakawa, Yuri Inoue, Aya Nakane-otani, Omar Samir, Akari Teramoto, Kaushalya Kulathunga, Manabu Kusakabe, Megumi NakamuraAbstract:Abstract The Transcription Factor MafB is specifically expressed in macrophages. We have recently demonstrated that MafB is expressed in anti-inflammatory alternatively activated M2 macrophages in vitro. Tumor-associated macrophages (TAMs) are a subset of M2 type macrophages that can promote immunosuppressive activity, induce angiogenesis, and promote tumor cell proliferation. To examine whether MafB express in TAMs, we analyzed green fluorescent protein (GFP) expression in Lewis lung carcinoma tumors of MafB-GFP knock-in heterozygous mice. FACS analysis demonstrated GFP fluorescence in cells positive for macrophage-markers (F4/80, CD11b, CD68, and CD204). Moreover, quantitative RT-PCR analysis with F4/80+GFP+ and F4/80+GFP− sorted cells showed that the GFP-positive macrophages express IL-10, Arg-1, and TNF-α, which were known to be expressed in TAMs. These results indicate that MafB is expressed in TAMs. Furthermore, immunostaining analysis using an anti-MafB antibody revealed that MafB is expressed in CD204-and CD68-positive macrophages in human lung cancer samples. In conclusion, MafB can be a suitable marker of TAMs in both mouse and human tumor tissues.
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MafB is a critical regulator of complement component C1q
Nature Communications, 2017Co-Authors: Mai Thi Nhu Tran, Michito Hamada, Hyojung Jeon, Yuki Tsunakawa, Megumi Nakamura, Risako Shiraishi, Keigo Asano, Motochika Hattori, Yuki Imamura, Risa FujiiAbstract:The Transcription Factor MafB is expressed by monocytes and macrophages. Efferocytosis (apoptotic cell uptake) by macrophages is important for inhibiting the development of autoimmune diseases, and is greatly reduced in MafB-deficient macrophages. Here, we show the expression of the first protein in the classical complement pathway C1q is important for mediating efferocytosis and is reduced in MafB-deficient macrophages. The efferocytosis defect in MafB-deficient macrophages can be rescued by adding serum from wild-type mice, but not by adding serum from C1q-deficient mice. By hemolysis assay we also show that activation of the classical complement pathway is decreased in MafB-deficient mice. In addition, MafB overexpression induces C1q-dependent gene expression and signals that induce C1q genes are less effective in the absence of MafB. We also show that MafB-deficiency can increase glomerular autoimmunity, including anti-nuclear antibody deposition. These results show that MafB is an important regulator of C1q.
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MafB is a critical regulator of complement component C1q
Nature Publishing Group, 2017Co-Authors: Mai Thi Nhu Tran, Michito Hamada, Hyojung Jeon, Yuki Tsunakawa, Megumi Nakamura, Risako Shiraishi, Keigo Asano, Motochika Hattori, Yuki Imamura, Risa FujiiAbstract:Complement component C1q activates efferocytosis, suppresses inflammatory responses, and is thereby thought to limit autoimmune disease. Here, the authors show that macrophage Transcription Factor MafB regulates total serum levels of C1q, which contributes to preventing autoimmune disease in mice
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Combinatorial motif analysis of regulatory gene expression in MafB deficient macrophages
BMC Systems Biology, 2011Co-Authors: Mariko Morita, Michito Hamada, Megumi Nakamura, Satoru TakahashiAbstract:Background Deficiency of the Transcription Factor MafB, which is normally expressed in macrophages, can underlie cellular dysfunction associated with a range of autoimmune diseases and arteriosclerosis. MafB has important roles in cell differentiation and regulation of target gene expression; however, the mechanisms of this regulation and the identities of other Transcription Factors with which MafB interacts remain uncertain. Bioinformatics methods provide a valuable approach for elucidating the nature of these interactions with Transcriptional regulatory elements from a large number of DNA sequences. In particular, identification of patterns of co-occurrence of regulatory cis -elements (motifs) offers a robust approach. Results Here, the directional relationships among several functional motifs were evaluated using the Log-linear Graphical Model (LGM) after extraction and search for evolutionarily conserved motifs. This analysis highlighted GATA-1 motifs and 5’AT-rich half Maf recognition elements (MAREs) in promoter regions of 18 genes that were down-regulated in MafB deficient macrophages. GATA-1 motifs and MafB motifs could regulate expression of these genes in both a negative and positive manner, respectively. The validity of this conclusion was tested with data from a luciferase assay that used a C1qa promoter construct carrying both the GATA-1 motifs and MAREs. GATA-1 was found to inhibit the activity of the C1qa promoter with the GATA-1 motifs and MafB motifs. Conclusions These observations suggest that both the GATA-1 motifs and MafB motifs are important for lineage specific expression of C1qa . In addition, these findings show that analysis of combinations of evolutionarily conserved motifs can be successfully used to identify patterns of gene regulation.
Yuki Tsunakawa - One of the best experts on this subject based on the ideXlab platform.
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Transcription Factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis.
Kidney International, 2020Co-Authors: Toshiaki Usui, Michito Hamada, Naoki Morito, Hossam H. Shawki, Yoshinori Sato, Hiroyasu Tsukaguchi, Hyojung Jeon, Manoj Kumar Yadav, Akihiro Kuno, Yuki TsunakawaAbstract:Focal segmental glomerulosclerosis (FSGS) is a common cause of steroid-resistant nephrotic syndrome. Spontaneous remission of FSGS is rare and steroid-resistant FSGS frequently progresses to renal failure. Many inheritable forms of FSGS have been described, caused by mutations in proteins that are important for podocyte function. Here, we show that a basic leucine zipper Transcription Factor, MafB, protects against FSGS. MafB expression was found to be decreased in the podocytes of patients with FSGS. Moreover, conditional podocyte-specific MafB-knockout mice developed FSGS with massive proteinuria accompanied by depletion of the slit diaphragm-related proteins (Nphs1 and Magi2), and the podocyte-specific Transcription Factor Tcf21. These findings indicate that MafB plays a crucial role in the pathogenesis of FSGS. Consistent with this, adriamycin-induced FSGS and attendant proteinuria were ameliorated by MafB overexpression in the podocytes of MafB podocyte-specific transgenic mice. Thus, MafB could be a new therapeutic target for FSGS.
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Transcription Factor MafB is a marker of tumor-associated macrophages in both mouse and humans.
Biochemical and Biophysical Research Communications, 2020Co-Authors: Manoj Kumar Yadav, Hyojung Jeon, Yuki Tsunakawa, Yuri Inoue, Aya Nakane-otani, Omar Samir, Akari Teramoto, Kaushalya Kulathunga, Manabu Kusakabe, Megumi NakamuraAbstract:Abstract The Transcription Factor MafB is specifically expressed in macrophages. We have recently demonstrated that MafB is expressed in anti-inflammatory alternatively activated M2 macrophages in vitro. Tumor-associated macrophages (TAMs) are a subset of M2 type macrophages that can promote immunosuppressive activity, induce angiogenesis, and promote tumor cell proliferation. To examine whether MafB express in TAMs, we analyzed green fluorescent protein (GFP) expression in Lewis lung carcinoma tumors of MafB-GFP knock-in heterozygous mice. FACS analysis demonstrated GFP fluorescence in cells positive for macrophage-markers (F4/80, CD11b, CD68, and CD204). Moreover, quantitative RT-PCR analysis with F4/80+GFP+ and F4/80+GFP− sorted cells showed that the GFP-positive macrophages express IL-10, Arg-1, and TNF-α, which were known to be expressed in TAMs. These results indicate that MafB is expressed in TAMs. Furthermore, immunostaining analysis using an anti-MafB antibody revealed that MafB is expressed in CD204-and CD68-positive macrophages in human lung cancer samples. In conclusion, MafB can be a suitable marker of TAMs in both mouse and human tumor tissues.
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Role of MafB in macrophages.
Experimental Animals, 2020Co-Authors: Michito Hamada, Hyojung Jeon, Manoj Kumar Yadav, Yuki Tsunakawa, Satoru TakahashiAbstract:The Transcription Factor MafB regulates macrophage differentiation. However, studies on the phenotype of MafB-deficient macrophages are still limited. Recently, it was shown that the specific expression of MafB permits macrophages to be distinguished from dendritic cells. In addition, MafB has been reported to be involved in various diseases related to macrophages. Studies using macrophage-specific MafB-deficient mice show that MafB is linked to atherosclerosis, autoimmunity, obesity, and ischemic stroke, all of which exhibit macrophage abnormality. Therefore, MafB is hypothesized to be indispensable for the regulation of macrophages to maintain systemic homeostasis and may serve as an innovative target for treating macrophage-related diseases.
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MafB is a critical regulator of complement component C1q
Nature Communications, 2017Co-Authors: Mai Thi Nhu Tran, Michito Hamada, Hyojung Jeon, Yuki Tsunakawa, Megumi Nakamura, Risako Shiraishi, Keigo Asano, Motochika Hattori, Yuki Imamura, Risa FujiiAbstract:The Transcription Factor MafB is expressed by monocytes and macrophages. Efferocytosis (apoptotic cell uptake) by macrophages is important for inhibiting the development of autoimmune diseases, and is greatly reduced in MafB-deficient macrophages. Here, we show the expression of the first protein in the classical complement pathway C1q is important for mediating efferocytosis and is reduced in MafB-deficient macrophages. The efferocytosis defect in MafB-deficient macrophages can be rescued by adding serum from wild-type mice, but not by adding serum from C1q-deficient mice. By hemolysis assay we also show that activation of the classical complement pathway is decreased in MafB-deficient mice. In addition, MafB overexpression induces C1q-dependent gene expression and signals that induce C1q genes are less effective in the absence of MafB. We also show that MafB-deficiency can increase glomerular autoimmunity, including anti-nuclear antibody deposition. These results show that MafB is an important regulator of C1q.
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MafB is a critical regulator of complement component C1q
Nature Publishing Group, 2017Co-Authors: Mai Thi Nhu Tran, Michito Hamada, Hyojung Jeon, Yuki Tsunakawa, Megumi Nakamura, Risako Shiraishi, Keigo Asano, Motochika Hattori, Yuki Imamura, Risa FujiiAbstract:Complement component C1q activates efferocytosis, suppresses inflammatory responses, and is thereby thought to limit autoimmune disease. Here, the authors show that macrophage Transcription Factor MafB regulates total serum levels of C1q, which contributes to preventing autoimmune disease in mice